ABSTRACT: Hepato/renal fibrocystic disease (HRFD) is caused by mutations in genes whose protein products are associated with cilia. Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (PKD) and mutations in PKHD1 cause autosomal recessive PKD. There are also a number of rare forms of HRFD, which may provide valuable insights into common/unique mechanisms for cystic development. Recent work has focused on understanding the cell signaling pathways that lead to HRFD. Although a number of candidate signaling pathways have been identified, the signaling events that lead to initiation and progression of HRFD have not been elucidated. There is currently no approved treatment for HRFD. The UAB P30 Center will provide the Investigator Base with state-of-the-art HRFD models from Core B which are informed by human HRFD mutational analysis from Core A. Core C will provided integrated physiology-proteomics- genomics characterization of HRFD models and Core D will provide evaluation of therapeutic efficacy of candidate drugs. Core C provides comprehensive services that are not typically available to HRFD investigators at their home institution. The over arching premise of Core C is that to understand HRFD and to test therapeutic compounds requires the ability to assess physiological readouts in both in vivo and in vitro systems. Cell signaling and drug efficacy will be tested in accelerated models of HRFD, which will include reduced renal mass hypertrophic signaling, toxins, and ischemia reperfusion. The First Aim is to characterize mouse models of HRFD in vivo. This will include measurements of ambulatory blood pressure, GFR, cystic progression, and renal damage/disease progression. Studies will be performed using multiphoton confocal imaging, using recently developed cilia tagged or biosensor (GCaMP Ca2+) mice. The Second Aim is to establish mTERT and hTERT immortalized cell lines from human HRFD patients and mice generated by Core B. This will involve early passage Telomerase Reverse Transcriptase (TERT) immortalization of cells to maintain cell physiology states. For human cell lines, genetic analysis will be performed to identify the specific gene mutation in conjunction with Core A. Core C will serve as a central repository for cell lines from a diverse array of HRFDs. The Third Aim will use integrated physiological and molecular approaches for characterization of HFRD cell lines. Multiple approaches will be used to study immortalized cell lines and to examine efficacy of drugs. The effects of flow on cell signaling and proliferative pathways will be assessed using biosensor cells, fluorescence probes, gene array, proteomic analysis, and RNAseq. Three-dimensional gel matrix systems will be used to study cystic growth in vitro. Electrophysiology and tubular perfusion will be used to study specific channels and assess electrolyte transport in HRFD. Core C serves as a valuable resource for the Investigator Base to define the cellular mechanism(s) that lead to cyst initiation and progression and to evaluate the efficacy of potential therapeutic agents that will be effective in treating HRFD.